Protein archeology—a 4 billion-year journey

Study by Prof. Dan Tawfik unearths an amino acid that gave birth to modern proteins



Date: September 9, 2020

Despite the many astounding achievements of the scientific community over the past few centuries, the seemingly basic question of how life on Earth emerged is one that has remained unanswered, confounding humans since time immemorial. How did this transition from a primordial soup of chemicals to a living organism occur? And what did the building blocks that would ultimately lead to life as we know it today look like billions of years ago?

Prof. Dan Tawfik from the Department of Biomolecular Sciences, in collaboration with Hebrew University’s Prof. Norman Metanis, set out to illuminate one poorly understood part of the evolutionary puzzle—namely, determining what the predecessors of modern proteins looked like.

Predating living cells, modern proteins are large, complex chains comprised of 20 amino acids that are essential for cell structure and function, and are involved in almost every biological function, including growth and development, healing and repair, normal digestion, and energy supply. But they weren’t always this way. Prof. Tawfik’s study found that one amino acid—called ornithine—was likely a key precursor to the proteins in the human body today. And moreover, its interaction with RNA—which helps code genes and convey genetic information—played a key role in creating the earliest life forms.

Earlier this year, Prof. Tawfik received the prestigious EMET Prize this year for his work on the evolution of proteins.

An amino acid that was history in the making

In 1952, scientists Stanley Miller and Harold Urey demonstrated that amino acids could spontaneously be generated by replicating the conditions of pre-life Earth. This famous experiment caused quite a stir in the scientific world and provided the first evidence that the organic molecules needed for life could be formed from inorganic components.

Of the assortment of molecules that arose from this experiment, the amino acids arginine, lysine and histidine—the three positively charged amino acids found in modern proteins—were not among them. These molecules are crucial for the development of living cells partly because they interact with the negatively charged DNA and RNA.

Prof. Tawfik’s research, however, centered around the one positively charged amino acid that was generated in the Miller-Urey experiment: ornithine. Ornithine exists in the body today, but it is not involved in the production process of modern proteins. However, it played a bigger role in human biological history: In fact, this one positively charged amino acid could be the missing link in the evolution of proteins, the study suggests.

After selecting protein sequences rich in arginine or lysine, Prof. Tawfik’s team modified them by replacing all their positively charged amino acids with ornithine. They found that these synthetic proteins bound weakly to DNA, but by subjecting them to simple chemical reactions that were likely available on Earth when life emerged, ornithine would convert to arginine. The more ornithine that was converted to arginine, the more the proteins started to resemble modern proteins and the stronger and more selective their bonds to DNA became.

The scientists took their experiment one step further and studied how these synthetic proteins interacted with RNA. They found that when presented with RNA, these orthinine-based molecules engaged in phase separation—an organizational process that could lead to the formation of simple compartments, or protocells, and eventually to living cells as we know them today. This discovery lends support to the Oparin-Haldane protocell theory, and suggests that the combination of RNA and amino acid chains had a role in the earliest life forms.

By reconstructing ancient proteins and understanding how they would have interacted with RNA, Profs. Tawfik and Metanis are helping us fill in the gaps in our understanding of life’s development on Earth.


Prof. Tawfik is supported by the Nella and Leon Benoziyo Professorial Chair